The mission of our Perimenopause in Brain Aging and Alzheimer's Disease Program Project is to discover the transformations that occur in the brain during the perimenopausal transition that can result in phenotypes predictive of risk for development of AD pathology. The Mission of Project 5 is to determine the mechanism the perimenopausal hot flash which is the most common symptom of menopause. The hot flash occurs in 60-85% of Western women during the perimenopausal transition. To date, the mechanism of the menopausal hot flash remains undetermined. We propose that the temperature dysregulatlon of the perimenopause is the result of a bioenergetic shift in the brain. Utilizing rodent models of human perimenopause, Project 5 will achieve its mission by determining: (1) in Aim 1 the physiological and bioenergetic phenotype of a preclinical model of the hot flash; (2) in Aim 2 the underlying neural mechanisms of the perimenopausal hot flash and (3) in Aim 3 the translational validity and potential of the proposed hot flash mechanism. To address our hypotheses, we will experimentally determine brain metabolism, lipidomic profile, mitochondrial function and bioenergetic gene expression during the period of perimenopausal temperature dysregulatlon. Network and pathway bioinformatic analyses will be conducted to generate an integrative systems level interpretation across experimental outcomes. Discovery of the mechanisms of action that underlie the perimenopausal hot flash will inform understanding of the neurobiological transformations that occur during this aging transition. Further, these mechanisms of action may inform understanding of potential risks for developing hypometabolism in brain and ultimately an at-risk-for Alzheimer's disease phenotype. From a translational perspective, determining the mechanism of the hot flash could generate multiple targets for rationally designed therapeutic interventions. Clinically, the hot flash remains an unresolved issue in women's health and affects women transitioning through natural or induced menopause, those undergoing treatment for uterine fibroids or therapy for breast cancer. Moreover, the hot flash is a common consequence of therapy for prostate cancer in men and of type 2 diabetes in both sexes. RELEVANCE: Why women experience the hot flash during menopause remains unknown. Project 5 of our Perimenopause Program Project will determine the mechanism of the menopausal hot flash to better understand this aging transition in women. Understanding why the menopausal hot flash occurs could also provide insights into why breast cancer and prostate cancer survivors and persons with type 2 diabetes also experience hot flashes and strategies to prevent and treat the hot flash developed.